dMyc Functions Downstream of Yorkie to Promote the Supercompetitive Behavior of Hippo Pathway Mutant Cells

Abstract

Genetic analyses in Drosophila epithelia have suggested that the phenomenon of “cell competition” could participate in organ homeostasis. It has been speculated that competition between different cell populations within a growing organ might play a role as either tumor promoter or tumor suppressor, depending on the cellular context. The evolutionarily conserved Hippo (Hpo) signaling pathway regulates organ size and prevents hyperplastic disease from flies to humans by restricting the activity of the transcriptional cofactor Yorkie (yki). Recent data indicate also that mutations in several Hpo pathway members provide cells with a competitive advantage by unknown mechanisms. Here we provide insight into the mechanism by which the Hpo pathway is linked to cell competition, by identifying dMyc as a target gene of the Hpo pathway, transcriptionally upregulated by the activity of Yki with different binding partners. We show that the cell-autonomous upregulation of dMyc is required for the supercompetitive behavior of Yki-expressing cells and Hpo pathway mutant cells, whereas the relative levels of dMyc between Hpo pathway mutant cells and wild-type neighboring cells are critical for determining whether cell competition promotes a tumor-suppressing or tumor-inducing behavior. All together, these data provide a paradigmatic example of cooperation between tumor suppressor genes and oncogenes in tumorigenesis and suggest a dual role for cell competition during tumor progression depending on the output of the genetic interactions occurring between confronted cells.

Tumor suppression by cell competition through regulation of the Hippo pathway

“…Elevation of Yki levels is sufficient to protect M +/− cells from cell competition and can even transform normal cells into supercompetitors (22,24,25). Remarkably, ex-lacZ, which was up-regulated in noncompeted scrib − clones, was not induced in scrib − clones surrounded by wild-type cells in most regions of eye and wing discs (Figs.…”

“…Importantly, elevated levels of Yki can rescue M +/− cells from being eliminated by cell competition and also can transform normal cells into supercompetitors that induce apoptosis in their neighbors and proliferate at their neighbors' expense (22,24,25). Yki may increase the competitiveness of cells by inducing the expression of Myc, a known regulator of cell competition (24)(25)(26)(27). However, the reports that scrib − cells have high levels of Yki activity and the hypothesis that scrib − cells are eliminated by cell competition present a paradox.…”

Drosophila Myc integrates multiple signaling pathways to regulate intestinal stem cell proliferation during midgut regeneration

“…We also provided evidence that tissue damage may regulate dMyc expression at a post-transcriptional level. Two recent studies suggest that Yki-Sd may directly regulate dMyc transcription in wing imaginal discs [33,34]. We identified a 1 kb dMyc enhancer (dMyc1.0) that contains multiple consensus Sdand Stat-binding sites and is capable of mediating the transcriptional regulation of a reporter gene (dMyc1.0-luc) by Yki-Sd and Stat in S2 cells.…”

The Hippo pathway regulates stem cell proliferation, self-renewal, and differentiation

“…The Hippo pathway also inhibits expression of a microRNA bantam to affect organ size, although the downstream effector of bantam is not clear. Furthermore, Yki-Sd was shown to transcriptionally induce dMyc, a potent promoter of ribosome biogenesis and cell growth (Neto-Silva et al, 2010;Ziosi et al, 2010), which may mediate the cell competition phenomenon observed in tissues with imbalance of Hippo pathway activity. In addition, Yki induces E2F1 (Goulev et al, 2008), which may be involved in cell-autonomous regulation of cell proliferation; the EGFR ligands Vein, Keren, and Spitz (Zhang et al, 2009b;Ren et al, 2010); the Jak/Stat pathway ligands Unpaired1/2/3 (Upd1/2/3) (Karpowicz et al, 2010;Ren et al, 2010;Shaw et al, 2010;Staley and Irvine, 2010), which could mediate non-cell-autonomous function of the Hippo pathway; and the Hippo pathway genes Ex, Kibra, Crb, and Fj (Cho et al, 2006;Hamaratoglu et al, 2006;Genevet et al, 2009;Genevet et al, 2010), which may constitute a signal feedback loop.…”